Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration

Wei Shao; Tiffany W. Todd; Yanwei Wu; Caroline Y. Jones; Jimei Tong; Karen Jansen-West; Lillian M. Daughrity; Jinyoung Park; Yuka Koike; Aishe Kurti; Mei Yue; Monica Castanedes-Casey; Giulia del Rosso; Judith A. Dunmore; Desiree Zanetti Alepuz; Björn Oskarsson; Dennis W. Dickson; Casey N. Cook; Mercedes Prudencio; Tania F. Gendron; John D. Fryer; Yong Jie Zhang; Leonard Petrucelli

doi:10.1126/science.abq7860

Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration

Wei Shao, Tiffany W. Todd, Yanwei Wu, Caroline Y. Jones, Jimei Tong, Karen Jansen-West, Lillian M. Daughrity, Jinyoung Park, Yuka Koike, Aishe Kurti, Mei Yue, Monica Castanedes-Casey, Giulia del Rosso, Judith A. Dunmore, Desiree Zanetti Alepuz, Björn Oskarsson, Dennis W. Dickson, Casey N. Cook, Mercedes Prudencio, Tania F. GendronJohn D. Fryer, Yong Jie Zhang, Leonard Petrucelli

Research output: Contribution to journal › Article › peer-review

Abstract

Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 (TBK1) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg²²⁸→His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72, TBK1, and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.

Original language	English (US)
Pages (from-to)	94-99
Number of pages	6
Journal	Science
Volume	378
Issue number	6615
DOIs	https://doi.org/10.1126/science.abq7860
State	Published - Oct 7 2022

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Shao, W., Todd, T. W., Wu, Y., Jones, C. Y., Tong, J., Jansen-West, K., Daughrity, L. M., Park, J., Koike, Y., Kurti, A., Yue, M., Castanedes-Casey, M., del Rosso, G., Dunmore, J. A., Alepuz, D. Z., Oskarsson, B., Dickson, D. W., Cook, C. N., Prudencio, M., ... Petrucelli, L. (2022). Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration. Science, 378(6615), 94-99. https://doi.org/10.1126/science.abq7860

Shao, W, Todd, TW, Wu, Y, Jones, CY, Tong, J, Jansen-West, K, Daughrity, LM, Park, J, Koike, Y, Kurti, A, Yue, M, Castanedes-Casey, M, del Rosso, G, Dunmore, JA, Alepuz, DZ, Oskarsson, B , Dickson, DW , Cook, CN , Prudencio, M , Gendron, TF, Fryer, JD, Zhang, YJ & Petrucelli, L 2022, 'Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration', Science, vol. 378, no. 6615, pp. 94-99. https://doi.org/10.1126/science.abq7860

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title = "Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration",

abstract = "Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 (TBK1) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg228→His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72, TBK1, and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.",

author = "Wei Shao and Todd, {Tiffany W.} and Yanwei Wu and Jones, {Caroline Y.} and Jimei Tong and Karen Jansen-West and Daughrity, {Lillian M.} and Jinyoung Park and Yuka Koike and Aishe Kurti and Mei Yue and Monica Castanedes-Casey and {del Rosso}, Giulia and Dunmore, {Judith A.} and Alepuz, {Desiree Zanetti} and Bj{\"o}rn Oskarsson and Dickson, {Dennis W.} and Cook, {Casey N.} and Mercedes Prudencio and Gendron, {Tania F.} and Fryer, {John D.} and Zhang, {Yong Jie} and Leonard Petrucelli",

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doi = "10.1126/science.abq7860",

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T1 - Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration

AU - Shao, Wei

AU - Todd, Tiffany W.

AU - Wu, Yanwei

AU - Jones, Caroline Y.

AU - Tong, Jimei

AU - Jansen-West, Karen

AU - Daughrity, Lillian M.

AU - Park, Jinyoung

AU - Koike, Yuka

AU - Kurti, Aishe

AU - Yue, Mei

AU - Castanedes-Casey, Monica

AU - del Rosso, Giulia

AU - Dunmore, Judith A.

AU - Alepuz, Desiree Zanetti

AU - Oskarsson, Björn

AU - Dickson, Dennis W.

AU - Cook, Casey N.

AU - Prudencio, Mercedes

AU - Gendron, Tania F.

AU - Fryer, John D.

AU - Zhang, Yong Jie

AU - Petrucelli, Leonard

PY - 2022/10/7

Y1 - 2022/10/7

N2 - Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 (TBK1) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg228→His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72, TBK1, and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.

AB - Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 (TBK1) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg228→His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72, TBK1, and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.

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Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration

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